Epitranscriptomic regulation of Notch signaling.

Abstract

Notch signaling is extensively controlled post-transcriptionally, yet the contribution of RNA chemical modifications has only recently begun to be resolved mechanistically. Here, we review epitranscriptomic regulation of Notch signaling, focusing on RNA modification-dependent control of the processing, localization, stability, translation, and editing of Notch-related transcripts. To distinguish direct transcript-level regulation from global pathway effects, we propose a four-step mechanistic framework requiring site-resolved modification mapping, modifier- or reader-dependent alteration of RNA fate, a corresponding change in Notch signaling output, and transcript-specific rescue or epistasis. Applying this framework further highlights reader identity as a key determinant of m6A directionality: YTHDF2-mediated recognition can promote transcript decay, whereas YTHDF1 and IGF2BP-family readers can enhance translation or transcript stability and thereby reinforce Notch signaling. Across developmental, stem-cell, cancer, neurobiological, and immune contexts, these mechanisms can tune both the intensity and persistence of Notch signaling. Because the available evidence remains strongly dominated by m6A, other RNA marks are discussed more cautiously. This transcript-centered framework separates direct epitranscriptomic regulation of Notch components from broader pathway rewiring and provides a basis for prioritizing mechanistically supported RNA-level therapeutic targets.